Current approaches and strategies to identify Hedgehog signaling pathway inhibitors for cancer therapy

The Hedgehog signaling pathway plays a vital role in embryonic development and tissue patterning. Aberrant regulation of this pathway is commonly associated with the occurrence, development and progression of various types of malignancies. The development of inhibitors targeting Hedgehog pathway has attracted significant interests in cancer therapy and led to the discovery of three drugs Vismodegib, Sonidegib and Glasdegib. However, their clinical application has been hampered due to adverse effects and resistance issues, highlighting the urgent need for new inhibitors. Herein we give a systematic overview of the current status and characteristics of various approaches to developing the Hedgehog pathway inhibitors, including library screening, natural product-oriented approach, analogue approach, drug repositioning, in silico tools and others. The future prospects are also discussed for the discovery and development of next-generation inhibitors.